This invention relates to methods for the treatment of arthritis, including both rheumatoid arthritis and osteoarthritis. In particular, this invention relates to such methods of treatment by the administration of bone-active phosphonate compounds and non-steroidal anti-inflammatory drugs (NSAIDs). The bone-active phosphonates and NSAIDS act in synergy with one another and their administration results in a reduction of inflammation, but also inhibits the destruction of bone and hard tissue in the intraarticular area of the joint, which permits repair of the sub-chondral bone and hard tissue.
Bone loss, or alteration in bone turnover, can result from, or be associated with, many types of arthritis, including rheumatoid arthritis and osteoarthritis. Rheumatoid arthritis is a chronic, systemic and articular inflammatory disorder characterized by weakening of the joint capsules and ligaments, followed by destruction of cartilage, ligaments, tendon and bone, and a decrease in viscosity and other alterations in the synovial membrane and fluid. Rheumatoid arthritis symptoms include systemic weakness, fatigue, localized pain, and stiffness, weakness, swelling, and deformation of the joints of the body. Rheumatoid arthritis is most common in women in the fourth to sixth decade of life.
The pathogenesis of rheumatoid arthritis, leading to the destruction of the joints, is characterized by two phases: 1) an exudative phase involving the microcirculation of the synovial cells that allow an influx of plasma proteins and cellular elements into the joint and 2) a chronic inflammatory phase occurring in the sub-synovium and sub-chondral bone, characterized by pannus (granulation tissue) formation in the joint space, bone erosion, and cartilage destruction. The pannus may form adhesions and scar tissue which causes the joint deformities characteristic of rheumatoid arthritis.
The etiology of rheumatoid arthritis remains obscure. Infectious agents such as bacteria and viruses have been implicated. A current hypothesis is that the Epstein-Barr (EBV) virus is a causative agent for rheumatoid arthritis.
Current rheumatoid arthritis treatment consists predominantly of symptomatic relief by administration of non-steroidal anti-inflammatory drugs (NSAIDs). NSAID treatment is mainly effective in the early stages of rheumatoid arthritis; it is unlikely it will produce suppression of joint inflammation if the disease is present for more than one year. Gold, methotrexate, immunosuppressants and corticosteroids have been tried with limited success.
On the other hand, osteoarthritis is an inherently non-inflammatory disorder of the movable joints characterized by deterioration and abrasion of articular cartilage, as well as by formation of new bone at the joint periphery. As osteoarthritis progresses, the surface of the articular cartilage is disrupted and wear-particles gain access to the synovial fluid which in turn stimulates phagocytosis by macrophage cells. Thus, an inflammatory response is eventually induced in osteoarthritis. Common clinical symptoms of osteoarthritis include cartilaginous and bony enlargements of the finger joints and stiffness on awakening and painful movement.
Common symptomatic treatments for osteoarthritis include analgesics, anti-inflammatories, disease-modifying arthritic drugs ("DMARDs"), steroids, and physical therapy.
A variety of polyphosphonic acid derivatives have been proposed for use in the treatment and prophylaxis of diseases involving abnormal calcium and phosphate metabolism. For example, numerous references disclose compositions containing polyphosphonates, in particular bisphosphonates, such as 1-hydroxyethylidene-diphosphonic acid ("EHDP"), and their use in inhibiting anomalous deposition and mobilization of calcium and phosphate in animal tissue: U.S. Pat. Nos. 3,683,080, issued Aug. 8, 1972 and 4,230,700, issued Oct. 28, 1980, both to Francis, and U.S. Pat. No. 4,868,164 to Ebetino, issued Sep. 19, 1989. Numerous other references describe substituted phosphonic acids useful for the treatment of osteoporosis and/or arthritis: U.S. Pat. Nos. 5,071,840 to Ebetino, et al, issued Dec. 10, 1991, 4,868,164, to Ebetino, et al., issued Sep. 19, 1989; 5,104,863, to Benedict, et al., issued Apr. 14, 1992; 4,267,108, to Blum et al., issued May 12, 1981; European Patent Application Publication No. 170,228, of Boehringer Mannheim GmbH, published Feb. 5, 1986; European Patent Application Publication No. 298,553, of Ebetino, published Jan. 11, 1989; U.S. Pat. Nos. 4,754,993, to Bosies, et al., issued Nov. 15, 1988; 4,939,130 to Jaeggi, et al., issued Jul. 3, 1990; 4,971,958 to Bosies, et al., issued Nov. 20, 1990; WO 90/12017 to Dunn, et al., published Oct. 18, 1990; WO 91/10646 to Youssefyeh, R., et al., published Jul. 25, 1991; AU-A-26738/88 to Jaeggi, K. A., publication date Jun. 15, 1989; AU-A-45467/89 of Ciba-Geigy, publication date May 31, 1990.
Suitable phosphonate compounds for use herein include those compounds described in the following references, all incorporated by reference herein: European Patent Application Publication No. 186,405, of Benedict and Perkins, published Jul. 2, 1986; sulfur-containing phosphonate compounds described in U.S. Patent to Breliere, et al., issued May 24, 1988; U.S. Pat. No. 4,876,247 to Barbier, et al., issued Oct. 24, 1989; European Patent Application Publication No. 100,718, of Breliere S. A., published Feb. 15, 1984; and those quaternary-nitrogen-continuing phosphonate compounds described in U.S. Pat. No. 4,208,401, Bauman (assigned to Colgate-Palmolive Co.), issued Jun. 17, 1980; and DE 40 11 777, Jaeggi, K., disclosed Oct. 18, 1990.
NSAIDs have been widely used in arthritis therapy for several years. The following references hereby incorporated by reference herein, describe various NSAIDs suitable for use in the invention described herein, and processes for their manufacture: U.S. Pat. No. 3,558,690 to Sallmann and Pfister, (assigned to Ciba Geigy), issued 1971; U.S. Pat. No. 3,843,681 (assigned to American Home Products), issued 1974; U.S. Pat. No. 3,766,263 to Godfrey, (assigned to Reckitt and Colman) issued 1973; U.S. Pat. No. 3,845,215 to Godfrey (assigned to Reckitt and Colman) issued 1974; U.S. Pat. No. 3,600,437 to Marshall (assigned to Eli Lilly), issued 1971; U.S. Pat. No. 3,228,831 to Nicholson and Adams, (assigned to Boots Pure Drug), issued 1966; (U.S. Pat. No. 3,385,886 to Nicholson and Adams, (assigned to Boots Pure Drug) issued 1968; U.S. Pat. No. 3,161,654 to Shen, (assigned to Merck & Co.), issued 1964; U.S. Pat. No. 3,904,682 to Fried and Harrison, (assigned to Syntex), issued 1975; U.S. Pat. No. 4,009,197 to Fried and Harrison, (assigned to Syntex), issued 1977; U.S. Pat. No. 3,591,584 to Lombardino (assigned to Pfizer) issued 1971; U.S. Pat. No. 5,068,458 to Dales et al., (assigned to Beecham Group, PLC.), issued Nov. 26, 1991; U.S. Pat. No. 5,008,283 to Blackburn et al. (assigned to Pfizer, Inc.), issued Apr. 16, 1991; and U.S. Pat. No. 5,006,547 to Loose (assigned to Pfizer), issued Apr. 9, 1991.
The administration of NSAIDs and bone-active phosphonates has been suggested as a method for enhancing the anti-inflammatory activity of NSAIDs. Such treatments using bisphosphonates and NSAIDs are disclosed in the following references, all hereby incorporated by reference herein, U.S. Pat. Nos. 4,269,828, to Flora, et al. issued May 26, 1981; 4,216,212, to Flora, et al., issued Aug. 5, 1980; 4,264,582 to Flora, et al., issued Apr. 28, 1981, 4,282,214, Flora, et al., issued Aug. 4, 1981.
Applicant has found that the administration of bone-active phosphonates and NSAIDs not only results in a reduction of inflammation, but also inhibits the destruction of bone and hard tissue in the intraarticular area of the joint, allows repair of the subchondral bone, and maintains and/or increases the range of motion of the joints. The NSAID active agent and the phosphonate active agent act in synergy. Accordingly, the benefits gained in the treatment of arthritis when utilizing the methods described herein are greater than is seen with either active agent, or their sum, if administered alone. The present methods result in a reduction in the amount of NSAIDS being administered to an arthritic patient, and in addition, also allow a reduction in the dosage of the phosphonate administered over time. The methods of this invention provide effective methods of treating arthritis, including osteoarthritis and rheumatoid arthritis, with reduced side effects compared to such methods known in the art.